Depressive disorders are a major public health problem, both in terms of personal suffering and socioeconomic burden. Epidemiological studies have emphasized the roles of genetic vulnerability and environmental factors in the emergence of depression. Unfortunately, the causes and pathophysiology of major depressive disorder remain largely unknown. Moreover, progress in understanding the neurobiology of depression is hindered by the lack of objective measures of core depressive symptoms. The goals of the proposed work are: (1) to investigate the neurobiological underpinnings of stress-induced anhedonia - an emerging endophenotype of depression - and the moderating effects of candidate genes previously linked to increased vulnerability to depression and stress sensitivity on these mechanisms;(2) to test the hypothesis that decreased phasic dopaminergic transmission within mesolimbic regions plays a key role in the pathophysiology of major depression, which will be achieved by using functional magnetic resonance imaging (fMRI) in conjunction with a pharmacological challenge;and (3) to investigate dopamine transporter (DAT) function and its relation to reward deficits in MDD using positron emission tomography (PET) and fMRI techniques. By combining molecular genetics, functional neuroimaging, pharmacological challenges, endocrinological assessments, and molecular imaging techniques, the proposed study is expected to provide novel insights into the pathophysiology of depression, and thus might offer new targets for treatment strategies and disorder prevention. PUBLIC HEALTH RELEVANCE: The current project proposes a combination of behavioral probes, molecular genetics, and functional and molecular neuroimaging techniques to investigate the role of dopaminergic dysfunction in major depression and in the cardinal symptom anhedonia - the loss of pleasure. This interdisciplinary approach is expected to provide novel insights into putative pathways associated with increased vulnerability to depression and anhedonia, and might provide novel targets for treatment strategies and prevention measures.